Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A
Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A
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DOI：
10.1074/jbc.m007383200
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发表时间：
2001-07-06
影响因子：
4.8
通讯作者：
Brownlee, M
中科院分区：
文献类型：
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作者：
Yamagishi, SI;Edelstein, D;Brownlee, M
瘦素是一种主要由脂肪组织分泌的循环激素，参与控制体重。血浆浓度与体重指数相关，据报道，胰岛素抵抗患者的血浆浓度较高，而胰岛素抵抗是心血管疾病的主要危险因素之一。然而，瘦素对血管壁细胞的直接作用尚不完全清楚。在这项研究中，我们研究了瘦素对牛主动脉内皮细胞（BAEC）活性氧（ROS）产生和单核细胞化学引诱蛋白-1 （MCP-1）表达的影响。我们发现瘦素以剂量依赖的方式增加BAEC中ROS的产生，并且其作用与葡萄糖的作用是可加性的。鱼鱼酮、壬基三氟丙酮（TTEA）、羰基氰化物间氯苯腙（CCCP）、锰（III）四酰（4-苯甲酸）卟啉（MnTBAP）、解偶联蛋白-1 (UCP1) hvj脂体或锰超氧化物歧化酶（MnSOD） hvj脂体完全阻止了瘦素的作用，表明ROS是由线粒体电子传递引起的。瘦素通过刺激肉碱棕榈酰基转移酶-1 （CPT-1）活性和抑制乙酰辅酶a羧化酶（ACC）活性来增加脂肪酸的转运，乙酰辅酶a羧化酶是脂肪酸氧化和合成的定速酶。瘦素诱导的ROS生成、CPT-1激活、ACC抑制和MCP-1过量产生被染料木素（酪氨酸激酶抑制剂H-89，蛋白激酶a （PKA）抑制剂）或十四烷基甘氨酸酯（CPT-1抑制剂）完全阻止。瘦素激活PKA，而其作用被cAMP拮抗剂Rp-cAMPS抑制，提示瘦素通过激活PKA增加脂肪酸氧化诱导ROS生成，可能在胰岛素抵抗型肥胖糖尿病患者动脉粥样硬化的进展中起重要作用。
Leptin, a circulating hormone secreted mainly from adipose tissues, is involved in the control of body weight. The plasma concentrations are correlated with body mass index, and are reported to be high in patients with insulin resistance, which is one of the major risk factors for cardiovascular disease. However, the direct effect of leptin on vascular wall cells is not fully understood. In this study, we investigated the effects of leptin on reactive oxygen species (ROS) generation and expression of monocyte chemoattractant protein-1 (MCP-1) in bovine aortic endothelial cells (BAEC). We found that leptin increases ROS generation in BAEC in a dose-dependent manner and that its effects are additive with those of glucose. Rotenone, thenoyltrifluoroacetone (TTEA), carbonyl cyanide m-chlorophenylhydrazone (CCCP), Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), uncoupling protein-1 (UCP1) HVJ-liposomes, or manganese superoxide dismutase (MnSOD) HVJ-liposomes completely prevented the effect of leptin, suggesting that ROS arise from mitochondrial electron transport. Leptin increased fatty acid orridation by stimulating the activity of carnitine palmitoyltransferase-1 (CPT-1) and inhibiting that of acetyl-CoA carboxylase (ACC), pace-setting enzymes for fatty acid oxidation and synthesis, respectively. Leptin-induced ROS generation, CPT-1 activation, ACC inhibition, and MCP-1 overproduction were found to be completely prevented by either genistein, a tyrosine kinase inhibitor, H-89, a protein kinase A (PKA) inhibitor, or tetradecylglycidate, a CPT-1 inhibitor. Leptin activated PKA, and the effects of leptin were inhibited by the cAMP antagonist Rp-cAMPS, These results suggest that leptin induces ROS generation by increasing fatty acid oxidation via PKA activation, which may play an important role in the progression of atherosclerosis in insulin-resistant obese diabetic patients.